Defective type I IFN immunity in mosquito-borne arboviral encephalitis

"At least 500 million people globally are infected annually by arboviruses. Among over 50 human pathogenic arboviruses, more than 30 of them are mosquito-borne. These arboviruses include many neurotropic RNA viruses that pose a growing and global threat to human populations. These arboviruses have been emerging and re-emerging particularly during the last seven decades, largely due to global ecological changes, including global warming and mass travel. The health and economic impact of arboviruses on affected communities is substantial, demanding urgent research to prevent further spread and reduce disease burden through targeted public health measures and novel therapeutic approaches. Although most infections are asymptomatic or benign, about 1/100 of the infected people develop severe disease, typically encephalitis. The immense interindividual clinical variability following infection by these viruses has remained largely unexplained. In this context, during the past 20 years, we have discovered single-gene inborn errors of immunity (IEIs) of 20 genes affecting the production of, or the response to, type I interferons (IFNs) in children and young adults with severe viral infections, especially influenza or COVID-19 pneumonia, and herpes simplex encephalitis. These findings led to our more recent discovery since 2020 that autoantibodies (auto-Abs) neutralizing type I IFNs (AAN-IFN-I), as phenocopies of IEIs, can underlie 5% and 15% of cases of critical influenza or COVID-19 pneumonia, and 10% and 40% of cases of Tick-borne encephalitis or West Nile virus (WNV) encephalitis, respectively, particularly in middle-aged and elderly adults. In the current project, we aim to test the hypothesis that defective type I IFN immunity, due to genetic deficiency or AAN-IFN-I, is a major determinant of severe neuroinvasive disease, especially encephalitis, following infection by mosquito-borne arboviruses. We will focus on three groups of such arboviruses that are emerging and re-emerging globally or particularly in Europe (including France) and Latin America (including Brazil and Mexico). First, we will enroll patients with severe disease, especially encephalitis, along with infected controls, following infection by 3 groups of mosquito-borne arboviruses: 1) the arboviruses of constant public health concern globally: WNV and Dengue fever virus (DENV); 2) two important viruses epidemic in tropical and sub-tropical continents: Zika virus (ZIKV) and CHIKV (CHIKV); 3) new outbreaks such as Oropouche virus. Virological and immunological studies will be carried out to clarify the related characteristic features in severe cases versus asymptomatic/mild infected controls. Second, we will search for defective type I IFN immunity, due to genetic deficiency or AAN-IFN-I, in patients with severe neuroinvasive disease, especially encephalitis, following infection by these arboviruses. Third, we will characterize the mechanisms of severe disease mechanism due to defective type I IFN immunity, at molecular and cellular levels, in ad hoc cell types relevant to these viral infections. We have already obtained exciting preliminary data, with the enrollment of ~185 encephalitis patients, and the finding of AAN-IFN-I in ~50%, 14% and 17% of WNV, CHIKV and ZIKV encephalitis cases, respectively. And strikingly, all the 9 women studied who were infected by ZIKV during pregnancy and gave birth to babies born with microcephaly were found to carry AAN-IFN-I. Our project is therefore highly innovative but supported by strong evidence. Elucidation of the role of type I IFN immunity in host defense against severe mosquito-borne arboviral infection will have major immunological, medical and public health impact globally."